We are following a volunteer cohort of 50,844 US and Puerto Rican women who were between the ages of 35 and 74 and had a sister with breast cancer but did not have breast cancer themselves when they joined the study between 2003 and 2009. At enrollment, data on potential risk factors and current health status were collected using computer assisted telephone interviews and mailed questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort is tracked annually for changes in vital status and major health outcomes. Detailed follow-up questionnaires on health outcomes, environmental and lifestyle exposures, and special topics are completed every 2-3 years. Medical records and tumor tissue (for breast cancer cases) are retrieved for those who develop cancer or other conditions of interest. The first Sister Study l follow-up survey was completed in June 2012; responses were obtained from 48,090 women for a response rate of 95%. The next round of detailed follow-up (January 2012 2014) is nearly complete with similarly high response rates. More than 2,000 women have reported a diagnosis of breast cancer or DCIS/LCIS. As expected, women in the cohort have, on average, twice the breast cancer risk as other US women. The overall ratio of observed to expected (based on age-specific US rates) breast cancer cases is currently 2.2, with slight differences for in situ (O/E 2.7) versus invasive (O/E 1.8) cancer. Patterns are similar for white, black, and Hispanic women. Consistent with other literature, the ratio of observed to expected cases is greatest for women who also have a mother with breast cancer and for those whose sisters were younger at diagnosis. Research studies using baseline and follow-up data are exploring risk factors for breast cancer and other health conditions. Recent papers have examined early life factors in relation to uterine fibroids in black women, age at menarche, and rheumatoid arthritis. In a study of urinary prostaglandin E2-metabolite (PGE-M) and breast cancer risk in 609 post-menopausal women (301 cases and 308 subcohort members), several known pro- and anti-inflammatory factors were associated with urinary PGE-M, and post-menopausal breast cancer risk was increased with increasing levels of urinary PGE-M among women who did not regularly use non-steroidal anti-inflammatory drugs (NSAIDs). These results support a role for prostaglandin E2 and inflammation in breast carcinogenesis, which may be modifiable by lifestyle and pharmacological interventions. Analyses are underway for a validation study of over 1,800 participants and their mothers aimed at evaluating how accurately women reported the information on early life collected at baseline, including information on their mothers pregnancy. Other studies in progress include early life factors and telomere length in peripheral blood and analyses examining several factors in relation to breast cancer risk including genetic variants, occupational organic solvent exposure, adiposity, and antibiotic use. Recent findings include an association between tubal ligation and menopausal symptoms, but not with age at menopause or breast cancer risk. We found six gene variants associated with relative telomere length in blood. Five of these variants are located in genes coding for proteins involved in DNA histone methylation and our results are consistent with other findings suggesting that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. We studied global DNA methylation using LINE-1 and found a small but significant inverse association between LINE-1 and breast cancer. We also found that higher levels of physical activity were associated with increased LINE-1 methylation. We measured DNA methylation at over 27,000 CpG sites in baseline blood samples from 298 breast cancer cases and 612 non-cases and identified 250 CpGs that were differentially methylated between cases and non-cases, with 75% of these CpGs under-methylated in cases. Methylation data were better at predicting subsequent breast cancer risk than traditional measures such as Gail score a measure that incorporates information on age, family history and other breast cancer risk factors. With co-investigators at the University of Washington, we completed geocoding participant addresses, and added data on air pollution levels at current and past residences of participants. A paper on air pollution and blood pressure has been submitted and studies of air pollution in relation to breast cancer and asthma risk are in progress. A new collaboration will add data on residential proximity to green space (parks, forests, farm land) and land use patterns for future studies of neighborhood factors and breast cancer risk. The Sister Study is collaborating with researchers from the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention (CDC) to study quality of life in breast cancer survivors. A survey completed in April 2012 covered breast cancer screening practices, family communication about cancer, and the effect of having a sister with breast cancer on Sister Study participants and their families; responses were collected from 20,000 women and data analysis is in progress. A second survey, completed in May 2013, involved women diagnosed with breast cancer and included topics that are of particular interest to younger women such as body image, work-life balance, relationships and intimacy, and fertility as well as questions related to breast cancer care and quality of life. Together, these surveys will increase our understanding of the impact of cancer on the lives of breast cancer survivors and their families and provide information that will help identify factors related to healthy living after diagnosis. The Sister Study participates in the NCI-sponsored Cohort Consortium, a group that facilitates the pooling of data from individual cohort studies to create databases large enough to investigate risk factors for rare cancers. The Sister Study is contributing to Cohort Consortium studies on head and neck, gallbladder and ovarian cancers, allowing us to contribute to research we could not address on our own. We are taking the lead on a new Consortium project on pregnancy-associated breast cancer and co-directing a Consortium project on risk factors for pre-menopausal breast cancer. A related study known as the Two Sister Study completed enrollment in December 2010. This family-based study on environmental and genetic risk factors for young onset breast cancer built on the Sister Study by recruiting the participant's sister with breast cancer (who completed Sister Study questionnaires and provided DNA) and their parents (who were asked to provide a saliva sample as a source of DNA). GWAS data for the Two Sister Study will be available shortly. Recent publications have concerned potential associations between fertility drugs and breast cancer and menopause symptoms in relation to breast cancer risk. A recently submitted paper on migraines and breast cancer included data from both the Two Sister Study and the Sister Study, providing an example of how to pool data from cohort and case-control studies. See Weinberg Z01-ES04400